Filipe Paula

Non-tumor necrosis factor-based biologic therapies for rheumatoid arthritis: present, future, and insights into pathogenesis.

The way rheumatoid arthritis is treated has changed dramatically with the introduction of anti-tumor necrosis factor (anti-TNF) biologics. Nevertheless, many patients still have less than adequate control of their disease activity even with these therapeutic regimens, and current knowledge fails to explain all the data already gathered. There is now a wide range of drugs from different classes of biologic disease-modifying anti-rheumatic drugs available (and soon this number will increase significantly), that provides the opportunity to address each patient as a particular case and thereby optimize medical intervention. Currently available biologics for the treatment of rheumatoid arthritis apart from anti-TNF-based therapies are reviewed, along with an analysis of the new insights they provide into the pathogenesis of the disease and a discussion of future prospects in the area.

Extended‐release niacin increases anti‐apolipoprotein A‐I antibodies that block the antioxidant effect of high‐density lipoprotein–cholesterol: the EXPLORE clinical trial

Aims Extended‐release niacin (ERN) is the most effective agent for increasing high‐density lipoprotein–cholesterol (HDL‐C). Having previously identified anti‐HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A‐I (aApoA‐I). Methods Twenty‐one patients older than 18 years, with HDL‐C ≤40 mg dl–1 (men) or ≤50 mg dl–1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12‐week periods, with 4 weeks of wash‐out before cross‐over. Primary outcome was change of paraoxonase‐1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA‐I antibodies. Clinical Trial Unique Identifier: EudraCT 2006–006889‐42. Results The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l–1, 95% confidence interval [CI] –9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL‐C levels (coefficient estimate 5.21 mg dl–1, 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl–1, 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl–1, 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA‐I antibodies (coefficient estimate 0.25 &mgr;g ml–1, 95% CI 0.09–0.40; P = 0.001). aApoA‐I titres at baseline were correlated with decreased PON activity. Conclusions The rise in HDL‐C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA‐I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.

Extended Release-Niacin increases anti-ApoA-I antibodies that block the anti-oxidant effect of HDL-C: the EXPLORE clinical trial.

Aims Extended‐release niacin (ERN) is the most effective agent for increasing high‐density lipoprotein–cholesterol (HDL‐C). Having previously identified anti‐HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A‐I (aApoA‐I). Methods Twenty‐one patients older than 18 years, with HDL‐C ≤40 mg dl–1 (men) or ≤50 mg dl–1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12‐week periods, with 4 weeks of wash‐out before cross‐over. Primary outcome was change of paraoxonase‐1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA‐I antibodies. Clinical Trial Unique Identifier: EudraCT 2006–006889‐42. Results The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l–1, 95% confidence interval [CI] –9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL‐C levels (coefficient estimate 5.21 mg dl–1, 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl–1, 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl–1, 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA‐I antibodies (coefficient estimate 0.25 &mgr;g ml–1, 95% CI 0.09–0.40; P = 0.001). aApoA‐I titres at baseline were correlated with decreased PON activity. Conclusions The rise in HDL‐C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA‐I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.